Formylation of 1, 3-dimethyl-4, 5-diaminouracil



Patented Aug. 14, 1951 UNITED STATES PATENT OFFICE FORMXLATION OF 1,3-DIMETHYL-4,5-

DIAMINOURACIL James ;.Ballantyne, Ferguson, Mo., assignor, to

Mallinckrodt Chemical Works, St. Louis, Mo., 3 a corporationxofy Missouri No Drawing. Application January 11, 1947, Serial No. 721,661

This invention relates: to methods of? formylation and more particularly to methods for formylating 1,3-dimethyl-4,5-diaminouracil.

Among the objects of this invention are the provision of an improved method for formylating 1,3-dimethyl-4,5-diaminouraci1; the provision. of a method of the type indicated which may be easily carried out; the provision. of a method. of the type referred-to whichis economical; and the provision ofa method of the type referred to which provides a product particularly adapted for subsequent processing. Other objects will be in part apparent and in part pointed out hereinaf 81".

The invention accordingly comprisesthe steps and sequence ofsteps, and features of synthesis, analysis, or metathesis, which will be-exemplified inthe processes hereinafter described, and the scope of the applicationof" which will be indicated in the following claims.

One of the steps in the customary preparation of purines such. as theophylline is the formation of the formyl derivative of1,3'-dimethyl.-4,5'-diaminouracil. This formylation has previously been carried out with concentrated formic acid. In general, the formic acid is of approximately 90% concentration, although slightly more dilute concentrations have been suggested. A substantial excess, which frequently is as high as 2,000%, is employed. In. every instance this excess has been substantial.

It-has now been found in accordance with the present invention that when much more dilute aqueous solutions of formic acid are employed such excessesof formic acid are unnecessary and that other important advantages are obtained. The formylating reagents of the present inventionare aqueous solutions of formic acid which contain not substantially in excess of 37% formic acid by weight. In general, it is preferred that these formylating reagents containampproximate- 1y 410% by weight of formic acid; Where such formylating agents are employed it has been found that the proportion of HCOOH employed to effect the formylation may be approximately the theoretical amount. A small excess, up to approximately one half mole per mole of diamino compound to be formylated, is preferred in order to obtain the best yields.

Among the important advantages of the present process are the economy in formic acid consumed, since recovery of the large excess of formic acid previously employed was very difiicult. In the present process it is practical to neutralize the small excess of formic acid and then recover the 8 Claims. (Cl. 260-260) formylated diamino compound by the subsequent steps in the preparation of the purine. The large excess of formic acid required by prior processes, and the alkali needed to neutralize it represent unnecessary. expense.

Moreover, it has been found that bythe use of the present process, not only is the consumption of formic acid materially reduced, but also it is unnecessary to isolate the formylated intermediate before clo-sing the ring to form theophylline.

The following examples illustrate the invention.

Example 1 A suspension of 20.4 grams (0.12 mole) of 1,3- dimethyl-4,5-diaminouracil in 220' ml. of water is acidified with 8' ml. 'of 87% formic acid (0.18 mole). This gives a 4% solution of formic acid. The solution is heated at 90 C. forthirtyminutes forming formyldimethyldiaminouracil in a yield comparable to that obtained by previously known methods. If desired, theformyl product can be isolated by cooling to induce crystallization or by other methods, but for most purposes this is not necessary. The resulting aqueous solutionof the formyl compound, after neutralization (aswith sodium hydroxide of the excess formic acid, is a highly desirable material from which to prep-are theophylline.

An additional amount-of? ION sodium hydroxide, amounting to 5% of the volume of the sol tion of formyl compounds, is added and the st: lution is heated to convert it to theophylline by well-known means. The solution may be acidifled and the theophylline allowed tocrystallize. The product is obtained in a yield of 83 of the theoretical based on' the amount of 1,3-dimethy1-4, 5-diaminouracil used as starting material. This yield is as high as has been obtained by any other method.

Example 2 1,3-dimethyl-4,5-diaminouracil (:10 grams) was dissolvedinhotwater (50; m1.) and acidified with 89% formic acid solution (5 ml). After stirring quickly, a mass of the formylated compound formed. The reaction mixture was heated two hours on a steam bath. The formyl derivative may be recovered by cooling the solution and allowing it to crystallize, or it may be converted to theophylline by neutralizing with a strong alkali, adding an excess, and heating as described in Example 1. After acidifying and cooling, the theophylline separated in crystalline form. The yield was 82% of the theoretical based on the dimethyldiaminouracil used as starting material.

making possible further savings.

3 Example 3 A suspension of 20.4 grams (0.12 mole) of 1,3- dimethyl-4,5-diaminouracil in 220 ml. of water was acidified with 106 ml. of 87% formic acid (2.4 moles). This solution contained 30% formic acid by weight. The solution of the diamino compound was heated at 90 C. for thirty minutes. The formyl compound can be isolated by cooling the solution and collecting the resulting solid.

To prepare theophylline from the solution of the formyl derivative, suflicient strong alkali is added to make the solution basic. A quantity of 10N sodium hydroxide equivalent to 5% of the total volume of the solution, is added and the resulting solution is heated at 90 C. for ten minutes to form theophylline.

The process of the present invention, as will be apparent from the foregoing, is relatively less expensive to carry out, particularly with respect to the formic acid consumed. A relatively small portion of formic acid is required when the dilute solutions of the present invention are used and the waste incident upon using concentrated formic acid in large excess is avoided. Moreover, the formylated compound is obtained in the form of an aqueous solution which is eminently suited to the subsequent ring closure to form theophylline in excellent yield. It is not necessary to isolate the formylated diamino compound, thereby subsequent ring closure is easily carried out after the neutralization of the small excess of formic acid which is preferably employed.

It will be apparent that less than the theoretical proportion of formic acid may be used if it is desired to formylate only part of the 1,3-dimethyl-4,5-diaminouracil.

In view of the above, it will be seen that the several objects of the invention are achieved and other advantageous results attained.

As many changes could be made in the above processes without departing from the scope of the invention, it is intended that all matter contained in the above description shall be interpreted as illustrative and not in a limiting sense.

I claim:

1. The method of formylating 1,3-dimethyl- 4,5-diaminouracil which comprises reacting said compound with an aqueous solution of formic acid containing not substantially in excess of 37% formic acid by weight, to form the formyl derivative of 1,3-dimethyl-4,5-diaminouracil.

2. The method of formylating 1,3-dimethyl- Finally, the 3 4,5-diaminouracil which comprises mixing said 4 formyl derivative of 1,3-dimethy1-4,5-diaminouracil.

4. The method of formylating 1,3-dimethyl- 4,5-diaminouraci1 which comprises mixing said compound with an aqueous solution containing approximately 1.5 molar'equivalents of formic acid of not substantially in excess of 10% concentration by weight, to form the formyl derivative of 1,3-dimethyl-4,5-diaminouracil.

5. The method of formylating 1,3dimethyl- 4,5-diaminouracil which comprises mixing said compound with an aqueous solution containing approximately 1.5 molar equivalents of formic acid of not substantially in excess of 37% by weight concentration, to form the formyl derivative of l,3-dimethyl-4,5diaminouracil.

6. The method of formylating 1,3-dimethyl- 4,5-diaminouracil which comprises mixing and heating said compound with an aqueous solution of formic acid to form the formyl derivative of 1,3-dimethyl-4,5-diaminouracil, said solution containing approximately 6% by weight of formic acid and being added in a ratio of approximately 1.5 molar equivalents and then neutralizing the excess formic acid remaining after said formylation.

7. The method which comprises mixing and heating 1,3-dimethyl-4,5-diaminouracil with an aqueous solution of formic acid to form the formyl derivative of 1,3-dimethyl-4,5-diaminouracil, said solution containing approximately 6% by weight of formic acid and being added in a ratio of approximately 1.5 molar equivalents, neutralizing the excess formic acid remaining after said formylation, adding an excess of a strong alkali to said neutralized product, and heating to form theophylline.

8. The method which comprises mixingand heating 1,3-dimethyl-4,5-diaminou.racil with an aqueous solution of formic acid to form the formyl derivative of 1,3-dimethyl-4,5-diaminouracil, said aqueous solution of formic acid containing not substantially in excess of 37% formic acid.

JAMES C. BALLANTYNE.

REFERENCES CITED The following references are of record in the file of this patent:

UNITED STATES PATENTS Name Date Engelmann Dec. 30, 1902 OTHER REFERENCES Number 

8. THE METHOD WHICH COMPRISES MIXING AND HEATING 1,3-DIMETHYL-4,5-DIAMINOURACIL WITH AN AQUEOUS SOLUTON OF FORMIC ACID TO FORM THE FORMYL DERIVATIVE OF 1,3-DIMETHYL-4,5-DIAMINOURACIL, SAID AQUEOUS SOLUTION OF FORMIC ACID CONTAINING NOT SUBSTANTIALLY IN EXCESS OF 37% FORMIC ACID. 